Single-Cell Dissection of Human Pancreatic Islet Dysfunction in Diabetes
Abstract
Type 2 diabetes (T2D) is a condition in which endocrine cells of the pancreas fail to secrete enough insulin to maintain proper blood sugar levels, leading to a wide range of health problems. T2D is a medical and public health crisis impacting the U.S. military Veteran, military beneficiary, and civilian populations. Strikingly, almost one in four (24%) Veterans receiving care at Department of Veterans Affairs (VA) clinics suffers from T2D, a rate approximately twice that of the general population (9.3%). Moreover, increased diabetes incidence among U.S. children threatens to erode the pool of Service-eligible individuals. T2D is a complex disease that results from both genetic and environmental factors, and its development and progression remain poorly understood. Improved diagnoses and treatments will require fundamental knowledge from careful genetic and physiologic analyses of the affected tissues. Past research has identified the pancreatic islets as important targets for diagnosis and treatment of T2D. The islets are clusters of at least five different specialized cell types that are critical for maintaining proper blood sugar, and their failure is central to the development of diabetes. Fundamental questions about the nature and order of events leading to islet failure remain unanswered. This is due, at least in part, to the mixed cell type composition of the islets, which makes it very difficult to fully account for physiological differences between healthy and diabetic islets, leading to complications of study results and interpretation. In this Discovery Award project, we will employ cutting-edge molecular approaches to overcome the technical hurdles that have limited our ability to analyze the islets at the cellular level. We will interrogate for the first time the programs controlling islet function and the mechanisms underlying islet failure at the level of the single cell. By generating molecular profiles and analyzing thousands of single islet cells in parallel, we will identify cell type-specific signatures and determine how they vary between nondiabetic and T2D islets. Cell type-specific signatures identified in this study will be further explored for the purposes of developing new tools for research and diagnostics, observing islet function in intact animals, and identifying new research avenues. Cell type-specific signatures that vary between non-diabetic and T2D islets will be evaluated both as biomarkers of islet stress and T2D and as druggable targets to prevent or treat T2D.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 31, 2017
- Source ID
- W81XWH1610130
Entities
People
- Michael L Stitzel
Organizations
- Jackson Laboratory
- United States Army